Molecular profiling of stem cell-derived retinal pigment epithelial cell differentiation established for clinical translation.
Molecular profiling of stem cell-derived retinal pigment epithelial cell differentiation established for clinical translation.
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DOI：
10.1016/j.stemcr.2022.05.005
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发表时间：
2022-06-14
影响因子：
5.9
通讯作者：
Lanner, Fredrik
中科院分区：
文献类型：
--
作者：
Petrus-Reurer, Sandra;Lederer, Alex R.;Baque-Vidal, Laura;Douagi, Iyadh;Pannagel, Belinda;Khven, Irina;Aronsson, Monica;Bartuma, Hammurabi;Wagner, Magdalena;Wrona, Andreas;Efstathopoulos, Paschalis;Jaberi, Elham;Willenbrock, Hanni;Shimizu, Yutaka;Villaescusa, J. Carlos;Andre, Helder;Sundstrom, Erik;Bhaduri, Aparna;Kriegstein, Arnold;Kvanta, Anders;La Manno, Gioele;Lanner, Fredrik
人胚胎干细胞来源的视网膜色素上皮细胞（human embryonic stem cells-derived retinal pigment epithelial cells，hESC-RPE）是治疗老年性黄斑变性（age-related macular degeneration，AMD）的一种有希望的细胞来源。尽管有几个正在进行的临床研究，在体外分化过程中的瞬态细胞状态的详细映射尚未进行。在这里，我们对已开发用于临床的hESC-RPE分化方案进行单细胞转录组分析。分化通过再现早期胚胎发育的培养多样化进行，由此细胞在向RPE谱系会聚之前迅速获得吻侧胚胎图案化特征。在中间步骤，我们鉴定并检查了NCAM 1+视网膜祖细胞群体的效力，并显示了该方案抑制非RPE命运的能力。我们证明，该方法产生的纯RPE池能够进一步成熟后，视网膜下移植在大眼动物模型。我们对hESC-RPE分化的评估支持开发安全有效的基于多能干细胞的AMD疗法。以体内细胞为基准的hESC-RPE分化的转录分析NCAM 1作为多能神经上皮祖细胞的细胞表面标志物出现hESC-RPE细胞通过发散-会聚过程获得，ESC-RPE在视网膜下注射到兔眼后在体内进一步成熟Lanner，La Manno
，他们发现干细胞来源的视网膜色素上皮细胞人胚胎干细胞（hESC-RPE）最初重演人视网膜胚胎阶段，在体外向>98% RPE收敛，并在体内进一步成熟。对多个细胞系和方案的转录组学分析提供了对分化过程中异质性动态的不同方面的见解。
Human embryonic stem cell-derived retinal pigment epithelial cells (hESC-RPE) are a promising cell source to treat age-related macular degeneration (AMD). Despite several ongoing clinical studies, a detailed mapping of transient cellular states during in vitro differentiation has not been performed. Here, we conduct single-cell transcriptomic profiling of an hESC-RPE differentiation protocol that has been developed for clinical use. Differentiation progressed through a culture diversification recapitulating early embryonic development, whereby cells rapidly acquired a rostral embryo patterning signature before converging toward the RPE lineage. At intermediate steps, we identified and examined the potency of an NCAM1+ retinal progenitor population and showed the ability of the protocol to suppress non-RPE fates. We demonstrated that the method produces a pure RPE pool capable of maturing further after subretinal transplantation in a large-eyed animal model. Our evaluation of hESC-RPE differentiation supports the development of safe and efficient pluripotent stem cell-based therapies for AMD. Transcriptional analysis of hESC-RPE differentiation benchmarked to in vivo cells NCAM1 emerges as a cell-surface marker of multipotent neuroepithelial progenitors hESC-RPE cells are obtained through a divergence-convergence process
hESC-RPE further mature in vivo upon subretinal injection into the rabbit eye Lanner, La Manno, and colleagues show that stem cell-derived retinal pigment epithelial cells (hESC-RPE) initially recapitulate human retinal embryonic stages, converge toward >98% RPE in vitro, and further mature in vivo. Transcriptomic analysis of multiple lines and protocols offer insights into different aspects of the heterogeneity dynamics during the differentiation process.
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